1. Field of the Invention
The present invention relates to methods of producing pyrrolidine derivatives. The purpose of the invention is to provide simple and efficient industrial production of pyrrolidine derivatives such as epoxypyrrolidines, pyrrolidinols, and the like. These pyrrolidine derivatives are important and useful synthetic intermediates for pharmaceuticals, and can be transformed to several kinds of pyrrolidine derivatives.
2. Description of the Prior Art
There are a few examples of forming 3,4-epoxypyrrolidines having formula (2) by epoxidizing the C.dbd.C double bond in 3-pyrrolines having formula (3). U.S. Pat. No. 3,657,274 discloses the use of trifluoroperacetic acid; Tetrahedron Letters 36, 1621 (1995) and Tetrahedron Letters 39, 8885 (1998), J. Org. Chem. 60, 398 (1995) disclose the use of m-CPBA (m-chloroperbenzoic acid) and Tetrahedron Letters 37, 3255 (1996) discloses the use of dioxiranes. All of these methods have the following problems: (1) highly dangerous peroxides are used in the reaction, (2) the processes of producing these peroxides are very complex and involve reagents which are hard to use in the industrial methods (e.g. 90% H.sub.2 O.sub.2), (3) in the group at the 1-position of 3-pyrrolines having formula (3), R.sup.1, is limited to the less basic compounds (such as amides, carbamates, and sulfamides) than ordinary cyclic amines (such as t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-toluenesulfonyl (Ts), and benzoyl (Bz) groups). This is why by-products of 3-pyrroline N-oxides are obtained selectively from ordinary cyclic amines with arakyl, aryl, and/or alalkyl groups at the 1-position of 3-pyrrolines.
On the other hand, there are a few examples in which epoxidation of basic 3-pyrrolines is disclosed. U.S. Pat. No. 4,230,718 discloses the formation of 3,4-epoxypyrrolidines via chlorohydrins, from 3-pyrrolines using aqueous HCl and Cl.sub.2 gas. Epoxidation of 3-pyrrolines using CH.sub.3 CN and H.sub.2 O.sub.2 is disclosed in J. Org. Chem. 47, 5196 (1982), and J. Chem. Soc., Chem. Commun. 293 (1995) discloses the use of BF.sub.3 /OEt.sub.2. Unfortunately, 3,4-dichloropyrrolidine by-products are formed in U.S. Pat. No. 4,230,718, and pyrrole by-products are formed in J. Org. Chem. 47, 5196 (1982). In the case of J. Chem. Soc., Chem. Commun. 293 (1995), both BF.sub.3 /OEt.sub.2 and dioxiranes are expensive and are difficult to use from the point of industrialization.
Therefore, these kinds of the oxidation reactions without limitation of substituents on nitrogen, and without production of by-products are unknown. Needless to say, nothing in the above reactions is useful for persulfates to be accelerated by irradiation.
Examples of the synthesis of 3-pyrrolidinols having formula (1) from 3,4-epoxypyrrolidines having formula (2) are found in Tetrahedron Letters 35, 7099 (1994), Tetrahedron Letters 39, 8885 (1998), J. Org. Chem 47, 5196 (1982), J. Org. Chem 60, 398 (1995) (by hydrolysis), and in U.S. Pat. No. 4,254,135 and German Patent No. 3,906,365 (by alcoholysis and aminolysis). These methods have the following disadvantages: (1) the synthesized 3,4-epoxypyrrolidines must be subjected to several isolation processes including distillation, crystallization, etc. to derivatize 3-pyrrolidinols, (2) total yields are low, (3) operation is inconvenient and costs are high.
(4) There is no known one-pot synthesis of 3-pyrrolidinols having formula (1) from 3-pyrrolines having formula (3).
One-pot synthesis of 3,4-dihydroxypyrrolidines from 3-pyrroline compounds is disclosed by J. Org. Chem. 60, 398 (1995), Tetrahedron Letters 35, 7099 (1998), and Tetrahedron Letters 28, 535 (1987) in which N-methylmorpholine N-oxides are used in the presence of osmium tetroxide (OsO.sub.4) or potassium permanganate (KMnO.sub.4). However, these methods have the following problems: (1) they are only available for the synthesis of cis-3,4-dihydroxypyrrolidines, (2) waste liquid, including oxidizing reagents of osmium tetroxide (OsO.sub.4) and potassium permanganate (KMnO.sub.4) can cause problems under certain circumstances.
There are a few examples of the synthesis of 3-pyrrolines having formula (3) with cyclization between cis-2-butene derivatives having formula (7) and primary amines having formula (8). In U.S. Pat. No. 3,657,274 cis-1,4-dichloro-2-butene (R.sup.8 .dbd.R.sup.9 .dbd.H; A.sup.1 .dbd.A.sup.2 .dbd.Cl) is used as a starting material. In Syn. Commun. 20, 227 (1990), cis-2-butene-1,4-diol dimethanesulfonylate (R.sup.8 .dbd.R.sup.9 .dbd.H, A.sup.1 .dbd.A.sup.2 .dbd.OSO.sub.2 CH.sub.3) is used as starting material. These methods have the following problems: (1) cis-1,4-dichloro-2-butene (R.sup.8 .dbd.R.sup.9 .dbd.H; A.sup.1 .dbd.A.sup.2 .dbd.Cl) is not only hard to produce industrially at low cost, but it is also a carcinogen, (2) cis-2-butene-1,4-diol dimethanesulfonylate (R.sup.8 .dbd.R.sup.9 .dbd.H; A.sup.1 .dbd.A.sup.2 .dbd.OSO.sub.2 CH.sub.3) is unstable in the air and decomposes metals.